H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation
H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation
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DOI：
10.1152/ajpheart.00934.2010
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发表时间：
2011-06-01
影响因子：
4.8
通讯作者：
Hrelia, Silvana
中科院分区：
文献类型：
--
作者：
Angeloni, Cristina;Motori, Elisa;Hrelia, Silvana
Angeloni C、Motori E、Fabbri D、Malaguti M、Leocini E、Lorenzini A、Hrelia S。H2O2 预处理通过 p38 MAPK 和 PI3K/Akt 激活调节 II 相酶。 Am J Physiol Heart Circ Physiol 300：H2196-H2205，2011。首次发表于 2011 年 4 月 8 日； doi: 10.1152/ajpheart.00934.2010.-缺血预处理是一种复杂的心脏保护现象，涉及细胞和分子的适应性变化，并以双相模式发生：1-2 小时后的早期阶段和 12-24 小时后的晚期阶段。虽然人们普遍认为活性氧与引发缺血预适应密切相关，但尚不清楚它们是否在预适应的早期或晚期发挥主要作用以及所涉及的机制。本研究旨在探讨 H2O2 诱导大鼠新生心肌细胞心脏保护作用的机制。我们重点关注抗氧化剂和 II 相酶及其通过蛋白激酶信号通路和核因子 E-2 相关因子 1 (Nrf1) 和 Nrf2 的调节。 H2O2预处理能够在适应后期比早期更有效地抵抗氧化应激。特别是，H2O2 预处理通过降低 caspase-3 活性、增加 Bcl2 表达以及通过 Nrf1 和 Nrf2 易位到细胞核选择性增加抗氧化剂和 II 相酶的表达和活性来抵消氧化应激诱导的细胞凋亡。小干扰RNA对Nrf1和Nrf2的下调降低了II相酶的表达水平。磷脂酰肌醇 3-激酶/Akt 和 p38 MAPK 激活的特异性抑制剂部分降低了 H2O2 预处理引起的心脏保护作用以及 II 相酶的诱导和活性。这些发现首次证明，Nrf1（而不仅仅是 Nrf2）在 H2O2 预处理触发的 II 相酶的诱导中发挥着关键作用。
Angeloni C, Motori E, Fabbri D, Malaguti M, Leoncini E, Lorenzini A, Hrelia S. H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation. Am J Physiol Heart Circ Physiol 300: H2196-H2205, 2011. First published April 8, 2011; doi: 10.1152/ajpheart.00934.2010.-Ischemic preconditioning is a complex cardioprotective phenomenon that involves adaptive changes in cells and molecules and occurs in a biphasic pattern: an early phase after 1-2 h and a late phase after 12-24 h. While it is widely accepted that reactive oxygen species are strongly involved in triggering ischemic preconditiong, it is not clear if they play a major role in the early or late phase of preconditioning and which are the mechanisms involved. The present study was designed to investigate the mechanisms behind H2O2-induced cardioprotection in rat neonatal cardiomyocytes. We focused on antioxidant and phase II enzymes and their modulation by protein kinase signaling pathways and nuclearfactor- E-2-related factor-1 (Nrf1) and Nrf2. H2O2 preconditioning was able to counteract oxidative stress more effectively in the late than in the early phase of adaptation. In particular, H2O2 preconditioning counteracted oxidative stress-induced apoptosis by decreasing caspase-3 activity, increasing Bcl2 expression and selectively increasing the expression and activity of antioxidant and phase II enzymes through Nrf1 and Nrf2 translocation to the nucleus. The downregulation of Nrf1 and Nrf2 by small interfering RNA reduced the expression level of phase II enzymes. Specific inhibitors of phosphatidylinositol 3-kinase/Akt and p38 MAPK activation partially reduced the cardioprotection elicited by H2O2 preconditioning and the induction and activity of phase II enzymes. These findings demonstrate, for the first time, a key role for Nrf1, and not only for Nrf2, in the induction of phase II enzymes triggered by H2O2 preconditioning.